A simple synthesis of 2,2′-bipyrroles from pyrrole

Article abstract of DOI:10.1016/j.tetlet.2008.10.034

2,2′-Bipyrroles, which are obvious precursors for the synthesis of 2,2′-bipyrrole-based natural products, are synthesized in three steps from pyrrole employing known pyrrolyl ketoalcohols by a sequential alcohol oxidation and Paal-Knorr pyrrole synthesis.

Full text of DOI:10.1016/j.tetlet.2008.10.034

Tetrahedron Letters 49 (2008) 7352–7354
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A simple synthesis of 2,20-bipyrroles from pyrrole
*
Liangfeng Fu, Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
a r t i c l e i n f o
a b s t r a c t
2,20-Bipyrroles, which are obvious precursors for the synthesis of 2,20-bipyrrole-based natural products,
are synthesized in three steps from pyrrole employing known pyrrolyl ketoalcohols by a sequential alco-
hol oxidation and Paal-Knorr pyrrole synthesis.
Article history:
Received 28 August 2008
Revised 7 October 2008
Accepted 8 October 2008
Available online 14 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2,20-Bipyrroles
Oxidation
Paal-Knorr pyrrole Synthesis
Bipyrroles are attractive and obvious precursors for the synthe-
sis of various polyhalogenated 1,20-1 and 1,30-bipyrroles2 found in
marine organisms and in several 2,20-bipyrrole-based natural
products3 (Fig. 1). Several new syntheses of 1,20-, 1,30-, and 2,20-
bipyrroles have been achieved in our laboratory in the context of
approaches to the environmentally significant and ubiquitous
naturally occurring polyhalogenated analogs (e.g., 1 and 2).
Unlike the relatively little studied 1,20- and 1,30-bipyrroles, syn-
theses of 2,20-bipyrroles have attracted the attention of a number
of different research groups since the beginning of the last century.
Previous syntheses of 2,20-bipyrroles include metal-catalyzed cou-
pling of halogenated pyrroles,4–11 such as palladium-4 and copper-
catalyzed5 coupling of iodopyrroles. 2,20-Bipyrroles can also be
synthesized by Suzuki coupling of boronopyrroles and pyrrolyltri-
flate,6 Paal-Knorr condensation,7 aza-Nazarov reaction,8 Trofimov
reaction,9 phenyliodine bis(trifluoroacetate)-mediated oxidative
coupling of pyrroles,10 nickel-catalyzed coupling of pyrroles,3d
and by other methods.11
Our recent work12 describing the Paal-Knorr reductive pyrro-
lylation of nitropyrroles in the presence of 1,4-diketones for the
synthesis of 1,20- and 1,30-bipyrroles prompted us to explore a
new and simple synthesis of 2,20-bipyrroles.
In the initial study, the known pyrrolyl ketoalcohol 4, which
was prepared by magnetization of pyrrole and reaction with buty-
rolactone, was oxidized with pyridine chlorochromate (PCC)13 in
methylene chloride to give the desired ketoaldehyde 515 in 92%
yield. After exploration of this Paal-Knorr reaction under various
conditions, we found that treatment of ketoaldehyde 5 with benz-
ylamine and acetic acid in methanol led to the desired 1-benzyl-
2,20-bipyrrole16 (6) in 81% yield (Scheme 1).
The same reaction of ketoaldehyde 5 with benzylamine and a
1:1 mixture of acetic acid and sodium acetate in toluene provides
bipyrrole 6 in a lower 68% yield.
i
ii
OH
N
H
N
H
O
Br
Br
OMe
3
4
Me
N
O
Ph
X
X
N
H
N
X
N
Me
iii
H
N
HN
Br
Br
N
H
N
H
R
O
1: X = Br
2: X = Cl
X = H, Br; R = H, alkyl
6
5
i: butyrolactone, MeMgI, tol, 89%;
ii: PCC, NaOAc, CH2Cl2, 92%;
Figure 1.
iii: PhCH2NH2, AcOH, MeOH, 81%
* Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646 3946.
E-mail address: GGribble@dartmouth.edu (G. W. Gribble).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.034

L. Fu, G. W. Gribble / Tetrahedron Letters 49 (2008) 7352–7354
7353
With these intial results in hand, other amines were allowed to
react with 5 and the N-methylpyrrole analog 7, and our results are
summarized in Scheme 2 and in Table 1. Both conditions A and B
give good results of 75% and 65% of product 8,16 respectively, when
p-methoxybenzylamine was employed (entries 3 and 4). Allyla-
mine gave the best yield of 96% of 916 when the reaction was con-
ducted in acetic acid and methanol (entry 5), while only 51% of 9 is
obtained using acetic acid and sodium acetate in toluene (entry 6).
Methylamine affords excellent yields of 10 (81% and 89%) under
conditions A and B. During our efforts to prepare the parent bipyr-
role 11,16–18 no 11 was obtained when ketoaldehyde 5 was treated
with ammonium acetate, acetic acid, and potassium acetate in tol-
uene. However, this reaction worked well when 5 was treated with
ammonium acetate in a 1:25 solution of 28% ammonium hydrox-
ide and ethanol (conditions C) (entry 9).
pared in two steps from N-methylpyrrole by lithiation14 with n-
butyllithium and TMEDA followed by quenching with butyrolac-
tone to give the corresponding ketoalcohol 1515 (not shown), and
subsequent oxidation with pyridinium chlorochromate (PCC)13 in
methylene chloride.
Methylamine in acetic acid and sodium acetate in toluene give
the best result for the preparation of bipyrrole 143d,16 (57% yield,
entry 14). Other amines such as benzylamine and allylamine give
bipyrroles 1216 and 1316 in lower yields (entries 10–13). A 49%
yield of 1011a,16 was obtained when 7 was treated with ammonium
acetate in ammonium hydroxide and ethanol.
Our results indicate that ketoaldehyde 5 is invariably superior
to 7 under these reaction conditions. For a synthesis of natural
bipyrrole 1, intermediate 14 was most efficiently obtained from
known ketoalcohol 4 in three steps (Scheme 3). Bipyrrole 14 was
generated in 91% yield from 10 by alkylation with iodomethane.
Exhaustive bromination of bipyrrole 14 with N-bromosuccinimide
in THF gave 13d in 78% yield.
Bipyrrole 14 is an important intermediate for the synthesis of
the natural products 1 and 2. Therefore, N-methylketoaldehyde 7
was targeted for the synthesis of bipyrrole 14. Thus, 715 was pre-
In summary, a relatively efficient and simple synthesis of 2,20-
bipyrroles using a modified Paal-Knorr condensation was devel-
oped, which is potentially useful for the synthesis of 2,20-bipyr-
role-based natural products, and is particularly attractive for the
synthesis of 2,20-bipyrroles with different N-substituents.
O
R1
N
R1NH2
H
N
R
N
R
30-96%
O
Acknowledgments
5: R = H
6, 8-24
7: R = Me
This work was supported by the Donors of the Petroleum Re-
search Fund (PRF), administrated by the American Chemical Soci-
ety, and by Wyeth.
Scheme 2.
References and notes
Table 1
Paal-Knorr condensation of 5 and 7 for the synthesis of 2,20-bipyrroles 6, 8–24
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Entry
R
R1
Condition
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
PhCH2
PhCH2
A
B
A
B
A
B
A
B
C
B
A
B
A
B
C
6
6
8
8
9
9
10
10
11
12
13
13
14
14
10
81
68
75
65
96
51
81
89
53
30
47
49
40
57
49
p-MeOPhCH2
p-MeOPhCH2
CH2CH@CH2
CH2CH@CH2
Me
Me
H
PhCH2
CH2CH@CH2
CH2CH@CH2
Me
Me
H
H
Me
Me
Me
Me
Me
Me
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631.
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Conditions A: amine, AcOH, MeOH, 40 °C; Conditions B: amine, AcOH, NaOAc, tolu-
ene, 60 °C; Conditions C: NH4OAc, 28% NH4OH, EtOH, 40 °C.
O
MeNH2, AcOH, NaOAc,
Me
N
toluene, 60 oC, 4 h
89%
H
N
H
N
H
O
10
5
Br
Br
Me
N
Me
N
NaH, MeI, DMF, 0 oC
91%
NBS, THF, -78 oC to r.t.
78%
Br
Br
Br
N
Me
N
Me
Br
14
1
Scheme 3.

7354
L. Fu, G. W. Gribble / Tetrahedron Letters 49 (2008) 7352–7354
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resulting mixture was heated to 40 °C under stirring for 48 h (the progress of
the reaction was monitored by TLC). After the completion of the reaction, it
was cooled to room temperature and poured into 1 M aqueous HCl (20 mL). It
was extracted with methylene chloride (4 ꢀ 20 mL), and the combined organic
extracts were washed with brine (20 mL) and dried over sodium sulfate.
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hexane/EtOAc (4:1) gave the desired 1-allyl-1H,10H-2,20-bipyrrole (9)
(129.5 mg, 96%) as a brown oil: 1H NMR (CDCl3): d 8.29 (br s, 1H), 6.74–6.84
(m, 2H), 6.24–6.31 (m, 4H), 5.99–6.14 (m, 1H), 5.23–5.27 (m, 1H), 5.00–5.14
(m, 1H), 4.61 (m, 2H); 13C NMR (CDCl3): d 135.5, 127.0, 124.2, 122.2, 118.1,
116.9, 109.5, 108.3, 107.7, 49.8; MS (EI): m/z (%) = 172 ([M+]), 157, 145, 131
(100), 117, 104, 98, 91, 85, 76, 63, 58; HRMS (EI): m/z calcd for C11H12N2:
172.1001, found: 172.1001.
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Compound 6: white solid (turns black upon standing); mp: 70–72 °C; 1H NMR
(CDCl3): d 8.01 (br s, 1H), 7.20–7.32 (m, 3H), 7.00 (m, 2H), 6.71 (m, 2H), 6.23
(m, 2H), 6.16 (m, 1H), 6.03 (m, 1H), 5.16 (s, 2H); 13C NMR (CDCl3): 139.2, 129.1,
127.7, 126.6, 126.5, 126.4, 122.8, 118.1, 109.5, 108.6, 108.0, 107.7, 51.0; MS
(EI): m/z (%) = 222 ([M+]), 205, 191, 168, 145, 131 (100), 104, 91, 58; HRMS (EI):
m/z calcd for C15H14N2: 222.1157, found: 222.1158.
Compound 8: Brown solid; mp: 69–70 °C; 1H NMR (CDCl3): d 8.19 (br s, 1H),
6.98 (m, 2H), 6.85 (m, 2H), 6.77 (m, 1H), 6.73 (m, 1H), 6.24 (m, 3H), 6.10 (m,
1H), 5.14 (s, 2H), 3.80 (s, 3H); 13C NMR (CDCl3): d 159.1, 131.0, 127.9, 127.1,
124.2, 122.6, 118.1, 114.4, 109.4, 108.4, 108.0, 107.7, 55.5, 50.5; MS (EI): m/z
(%) = 252 ([M+]), 180, 121 (100), 104, 76; HRMS (EI): m/z calcd for C16H16ON2:
252.1263, found: 252.1263.
Compound 12: Yellow oil; 1H NMR (CDCl3): d 7.25–7.29 (m, 3H), 6.93 (m, 2H),
6.83 (m, 1H), 6.67 (m, 1H), 6.28 (m, 1H), 6.24 (m, 1H), 6.17 (m, 1H), 6.12 (m,
1H), 5.02 (s, 2H), 3.27 (s, 3H); 13C NMR (CDCl3): d 138.9, 128.7, 127.5, 127.2,
125.1, 124.9, 122.8, 122.3, 111.4, 110.9, 108.1, 107.6, 51.0, 34.3; MS (EI): m/z
(%) = 236 ([M+]), 195, 159, 145 (100), 117, 91; HRMS (EI): m/z calcd for
C16H16N2: 236.1314, found: 236.1312.
Compound 13: Yellow oil; 1H NMR (CDCl3): d 6.73–6.80 (m, 2H), 6.18–6.27 (m,
4H), 5.84–5.96 (m, 1H), 5.13–5.16 (m, 1H), 4.95–4.99 (m, 1H), 4.42 (m, 2H),
3.51 (s, 3H); 13C NMR (CDCl3): d 135.1, 125.0, 124.9, 122.9, 121.7, 116.9, 110.9,
110.8, 107.9, 107.6, 49.5, 34.6; MS (EI): m/z (%) = 186 ([M+], 100), 171, 145, 117,
91, 71; HRMS (EI): m/z calcd for C12H14N2: 186.1157, found: 186.1157.
Compound 14:3d Yellow oil; 1H NMR (CDCl3): d 6.74 (m, 2H), 6.18–6.23 (m,
4H), 3.54 (s, 6H); 13C NMR (CDCl3): d 125.3, 122.9, 110.7, 107.6, 34.7.
17. Representative procedure (10) (conditions B): To a solution of ketoaldehyde 5
(66.5 mg, 0.44 mmol) in toluene (5 mL) were added methylamine (1.1 mL, 2 M
solution in methanol, 2.2 mmol), sodium acetate (37.0 mg, 0.44 mmol), and
acetic acid (27.0 mg, 0.44 mmol). The resulting mixture was heated to 60 °C
under stirring for 4 h (the progress of the reaction was monitored by TLC). The
mixture was cooled to room temperature and poured into 1 M aqueous HCl. It
was extracted with methylene chloride (4 ꢀ 20 mL), and the combined organic
extracts were washed with brine (20 mL) and dried over sodium sulfate.
Removal of solvent and flash column chromatography over silica gel with
hexane/EtOAc (4:1) gave the desired product 1011a (57.0 mg, 89%) as a brown
oil (solid upon standing); 1H NMR (CDCl3): d 8.25 (br s, 1H), 6.84 (m, 1H), 6.73
(m, 1H), 6.35 (m, 1H), 6.30 (m, 1H), 5.24 (m, 2H), 3.74 (s, 3H); 13C NMR (CDCl3):
d 127.4, 124.6, 123.3, 118.0, 109.5, 107.9, 107.2, 107.0, 35.4.
13. Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1988, 5, 235–240.
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15. Compound 5: White solid; mp: 67–69 °C; 1H NMR (CDCl3): d 10.0 (br s, 1H),
9.87 (s, 1H), 7.04 (m, 1H), 6.99 (m, 1H), 6.28 (m, 1H), 3.17 (t, J = 6.6 Hz, 2H),
2.87 (t, J = 6.6 Hz, 2H); 13C NMR (CDCl3): d 201.1, 188.5, 131.5, 125.4, 116.9,
111.0, 38.1, 30.4; MS (EI): m/z (%) = 151 ([M+]), 123, 94 (100), 66; HRMS (EI):
m/z calcd for C8H9NO2: 151.0633, found: 151.0632.
18. Representative procedure (11) (conditions C): To a solution of ketoaldehyde 5
(91.5 mg, 0.61 mmol) in a prepared solution of 28% NH4OH in ethanol (1:25,
20 mL) was added ammonium acetate (470 mg, 6.1 mmol). The resulting
mixture was heated to 40 °C under stirring for 48 h (the progress of the
reaction was monitored by TLC). The mixture was cooled to room temperature,
and poured into saturated NaCl (20 mL). It was extracted with EtOAc
(4 ꢀ 20 mL), and the combined organic extracts were dried over Na2SO4.
Removal of solvent and flash column chromatography over silica gel with
hexane/EtOAc (4:1) gave the desired product 1110 (42.4 mg, 53%) as a white
solid: white solid; mp 186–187.5 °C (lit.19 mp 187–189 °C); 1H NMR (CDCl3): d
8.44 (br s, 2H), 6.77 (m, 2H), 6.21–6.26 (m, 4H); 13C NMR (CDCl3): d 126.2,
117.7, 109.6, 103.7.
Compound 15: Yellow oil; 1H NMR (CDCl3): d 6.97 (m, 1H), 6.77 (m, 1H), 6.08
(m, 1H), 3.89 (s, 3H), 3.65 (t, J = 6.1 Hz, 2H), 3.10 (br s, 1H), 2.89 (t, J = 7.1 Hz,
2H), 1.89–1.92 (m, 2H); 13C NMR (CDCl3): d 191.8, 131.5, 130.7, 119.8, 108.2,
62.4,38.0, 36.0, 28.0; MS (EI): m/z (%) = 167 ([M+]), 150, 123, 108 (100), 85;
HRMS (EI): m/z calcd for C9H13O2N: 167.0946, found: 167.0946.
Compound 7: Yellow oil; 1H NMR (CDCl3): d 9.88 (s, 1H), 7.02 (m, 1H), 6.81 (m,
1H), 6.13 (m, 1H), 3.92 (s, 3H), 3.16–3.19 (t, J = 6.5 Hz, 2H), 2.83 (t, J = 6.5 Hz,
2H); 13C NMR (CDCl3): d 201.4, 188.6, 131.4, 130.3, 119.5, 108.4, 38.1, 37.9,
31.5; MS (EI): m/z (%) = 165 ([M+]), 137, 108 (100), 80; HRMS (EI): m/z calcd for
C9H11O2N: 165.0790, found: 165.0791.
19. Dohi, T.; Morimoto, K.; Ito, M.; Kita, Y. Synthesis 2007, 2913–2919.
16. Representative procedure (9) (conditions A): To
a solution of pyrrolyl
ketoaldehyde (5) (118.9 mg, 0.79 mmol) in methanol (8 mL) were added